ABSTRACT Huntington's disease (HD) is a devastating and invariably fatal progressive neurodegenerative disease characterized by atrophy and loss of selective neurons, axonal degeneration, and reactive gliosis, causing motor, cognitive, and psychiatric disorders. Currently, no curative treatment exists for this disease. A major obstacle for the development of HD therapeutics is the lack of sensitive and specific biomarkers that can quantitatively measure early brain changes, limiting real-time interpretation in HD clinical trials. The long-term goal of this study is to develop sensitive and specific noninvasive biomarkers that can accurately and quantitatively reflect disease progression and measure the effectiveness of new therapeutic interventions for HD to facilitate clinical trials. The objective of this proposal is to establish diffusion basis spectrum imaging (DBSI) metrics as new biomarkers for HD in mouse models through cross-correlation of longitudinal and cross- sectional DBSI analyses with histological, neurological, and functional assessments. DBSI is a novel diffusion magnetic resonance imaging (MRI)-based methodology recently developed by our group and substantially improves on the limitations of current MR-based imaging. Through multiple-tensor modeling of diffusion- weighted MRI signals, DBSI can differentiate and quantitatively assess coexisting multiple pathologies?axonal degeneration, myelin deficits, and neuroinflammation-associated changes in cellularity?with high sensitivity and specificity. Based on the capabilities of DBSI, we hypothesize that pathologies in premanifest and manifest HD mice can be accurately assessed by DBSI and that DBSI-defined abnormalities correlate with neurological and functional impairment in HD mice. This hypothesis will be tested by 1) identifying the progressive, DBSI- defined microstructural changes in HD mouse brains longitudinally and 2) determining the relationship among DBSI pathological metrics, HD brain pathology, and neurological impairment in HD mice through cross- sectional analysis. In addition, the relationship between DBSI pathological metrics and white matter function will be determined using a new diffusion-based functional MRI technique. These innovative experiments will establish new noninvasive, quantitative biomarkers of progressive neuropathology, white matter function, and neurological impairment in HD as well as provide important insights into the pathological mechanisms underlying neurological phenotypes in HD in vivo. The impact will be significant because our approach represents a substantial departure from current biomarker work in this disease, with the potential to provide substantial benefit in future clinical trials.